Career Development: The applicant's primary interest is the study of the functional mechanism of drug-induced hypnosis and analgesia in the human brain, thereby making a unique contribution to the study of anesthesia and its clinical components. These goals are the continuation of the applicant's preliminary research curriculum (K-30) and will consist of advanced training in psychometric methods, clinical research design, biostatistical theory and functional brain imaging methods. The research environment consists of a dedicated clinician-mentor with ongoing NIH support in the study of pain, a team of experienced scientific advisors and the proven institutional record of interdisciplinary research. Research Objective: In recent years, scientists and clinicians have worked towards a better understanding of drug-induced sedation, hypnosis and analgesia. The clinical objective has been to define a safe level of anesthesia while minimizing the cardiocirculatory, pulmonary, and cognitive effects of excessive anesthetics. We plan to investigate the clinical (psychometric) effect of drug-induced sedation on pain perception. Because the anterior cingulate cortex (ACC) of the brain responds to pain stimuli in a graded manner, suggesting its possible importance in pain perception, we plan to utilize functional brain imaging methods to quantify regional cerebral perfusion to the ACC. Research Hypothesis and Specific Aims: To test the hypothesis that sedative-hypnotic drugs enhance pain perception, we propose the following specific aims: 1) to contrast and compare in a quantitative fashion, using established psychometric methods, the dose-dependent effect of two GABA-acting (propofol and midazolam) and one alpha-2-receptor agonist (dexmedetomidine) sedative drugs on the sensory-discriminative and the hedonic component of pain perception, and 2) to delineate the effects of these sedative on regional cerebral blood flow (rCBF) and blood oxygen level dependent (BOLD) magnetic resonance signal intensity in the ACC, SI and Sll (regions of interest - pain) and the PCC, hippocampus and thalamus (regions of interest - sedation) in response to painful thermal stimuli with the use of two complementary brain imaging modalities, single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI). [unreadable] [unreadable] [unreadable]